Use of solid pharmaceutical compositions comprising meloxicam

Abstract

To provide novel dosage forms for improving pharmacokinetics or bioavailability of therapeutically active compounds in treatment of diseases such as pain and inflammation.SOLUTION: A dosage form comprises meloxicam, a sulfobutylether-β-cyclodextrin (SBEβCD), a bicarbonate, and a triptan. The dosage form is an oral dosage form having a shorter Tmax of meloxicam than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain the SBEβCD and 3) does not contain the bicarbonate. A tablet in which meloxicam with low solubility in water is formed into an inclusion complex with a sulfobutylether-β-cyclodextrin and further blended with a bicarbonate such as K2CO3 and NaHCO3 as a buffering agent is improved in the solubility and pharmacokinetic properties (bioavailability, Tmax, and the like) of meloxicam.SELECTED DRAWING: Figure 11

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 504,105, filed May 10, 2017, and U.S. Provisional Patent Application No. 62 / 536,466, filed July 25, 2017, and of International Application No. PCT / US2018 / 012433, filed January 4, 2018, all of which are incorporated by reference in their entireties. [Background technology]

[0002] There is a continuing need for therapeutic approaches with improved efficacy in the treatment of pain, inflammation, and related disorders. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure relates to the use of bicarbonates and / or cyclodextrins, such as sulfobutyl ether β-cyclodextrin (SBEβCD), to improve the pharmacokinetics or bioavailability of drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), such as meloxicam, triptans, such as rizatriptan, or combinations thereof.

[0004] For example, some embodiments include a dosage form containing a triptan (such as rizatriptan or frovatriptan) in combination with a cyclodextrin (optionally as an inclusion complex of the triptan and cyclodextrin) and / or a bicarbonate, and methods of treatment using the dosage form.

[0005] Some embodiments include a dosage form containing meloxicam, sulfobutyl ether β-cyclodextrin (SBEβCD), a bicarbonate, and a triptan, which has a lower T of meloxicam than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain a bicarbonate. maxThis includes dosage forms that are short oral dosage forms.

[0006] Some embodiments include an inclusion complex of a triptan (such as rizatriptan or frovatriptan) within a cyclodextrin.

[0007] Some embodiments include dosage forms that contain 1) an inclusion complex of a triptan (such as rizatriptan or frovatriptan) and a cyclodextrin, or 2) a triptan (such as rizatriptan or frovatriptan) and a carbonate or bicarbonate.

[0008] Some embodiments include a method of administering a product that includes a triptan in combination with 1) a cyclodextrin, and / or 2) a buffering agent. In some embodiments, the method includes treating a patient with a pharmaceutical formulation that includes a triptan (such as rizatriptan or frovatriptan) and a cyclodextrin and / or a carbonate / bicarbonate. Some embodiments may also include increasing the bioavailability of the triptan (such as rizatriptan or frovatriptan) or increasing the percentage of the triptan that is bioavailable in a subject in need of the triptan compared to a formulation that does not include a cyclodextrin or a carbonate / bicarbonate.

[0009] Some embodiments include a method of improving the pharmacokinetics of a triptan or NSAID comprising orally administering to a mammal or human in need of treatment with a triptan or NSAID a dosage form described herein.

[0010] Some embodiments include a method of treating pain comprising orally administering a dosage form described herein to a mammal or human in need of such treatment. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows the results described in Example 2 and shown in Table 6. [Diagram 2]Another figure showing the results described in Example 2 and shown in Table 6. [Diagram 3] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 4] Another figure showing the results described in Example 2 and shown in Table 6. [Diagram 5] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 6] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 7] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 8] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 9] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 10] Another figure showing the results described in Example 2 and shown in Table 6. [Figure 11] FIG. 2 is a plot of meloxicam plasma concentrations at various time points over the first 24 hours for an embodiment of a dosage form described herein and a commercially available meloxicam dosage form. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Meloxicam and other NSAIDs, as well as other drugs, have poor aqueous solubility, which can reduce bioavailability and delay the onset of analgesia. One method of increasing the solubility and bioavailability of meloxicam and other drugs is through the use of cyclodextrins in combination with meloxicam.

[0013] This may generally be accomplished using a dosage form (e.g., an oral dosage form) that contains a triptan (e.g., rizatriptan), optionally in combination with an NSAID (e.g., meloxicam), along with 1) a cyclodextrin (optionally in the form of an inclusion complex), and / or 2) a buffering agent (e.g., a bicarbonate). Administering this type of dosage form to a patient may increase the bioavailability of the triptan (e.g., rizatriptan) or NSAID (e.g., meloxicam) in the patient, increase the rate at which the triptan (e.g., rizatriptan) or NSAID (e.g., meloxicam) becomes bioavailable, or increase the rate at which the plasma concentration of the triptan or NSAID increases. For example, the triptan or NSAID may have a shorter T max or increased C max or the area under the plasma concentration curve (AUC).

[0014] Any suitable triptan may be used, such as sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, alvitriptan, zolmatriptan, etc. (including combinations or salts thereof). In some embodiments, the triptan comprises rizatriptan, which has the following structure:

[0015] [ka]

[0016] NSAIDs include, but are not limited to, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered to be an NSAID for the purposes of this disclosure), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, meloxicam, pinoxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, phenylbutazone, or combinations thereof.

[0017] In some embodiments, the NSAID is meloxicam, which has the structure:

[0018] [ka]

[0019] Meloxicam exhibits anti-inflammatory, analgesic, and antipyretic effects. The mechanism of action of meloxicam may be related to the inhibition of prostaglandin synthesis enzymes (cyclooxygenase, COX) involved in the first step of the arachidonic acid cascade, which leads to reduced formation of prostaglandins, thromboxanes, and prostacyclin.

[0020] Dosage forms may be given enterally (for example, but not limited to, oral, sublingual, or rectal delivery) or parenterally (for example, but not limited to, intravenous, intramuscular, nasal, or subcutaneous delivery).

[0021] The term "treatment" broadly includes any kind of therapeutic activity (such as the diagnosis, cure, mitigation, or prevention of disease in humans or other animals) or any activity that otherwise affects the structure or any function of the human or animal body.

[0022] The dosage form can be used to treat or ameliorate any type of pain. Such pain includes, but is not limited to, migraine and other types of headaches, inflammatory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute pain, localized pain, generalized pain, cancer pain, acute pain, pain due to injury, pain due to disease (e.g., fever), post-operative pain, etc. In some cases, pain relief may be temporary, or pain relief may be provided independent of improvement of the disease or disease or improvement of the underlying cause of the disease or disease. For example, an individual suffering from a disease may experience pain relief even though the underlying disease does not improve or continues to progress. In some embodiments, the pain affects muscles, nerves, cartilage, bone, ligaments, tendons, tendon sheaths, bursae, or joints.

[0023] Migraine is a headache disorder characterized by frequent headaches that can be moderate to severe. The headaches may affect one side of the head, may be pulsating in nature, and may last from 2 to 72 hours. Accompanying symptoms include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), and smell. The pain may be worsened by physical activity. Migraine may be accompanied by aura, which can be a brief visual disturbance that signals an upcoming headache.

[0024] For some methods, the dosage form may be administered to relieve inflammatory pain, such as inflammatory musculoskeletal pain, pain due to injury, arthritis pain, and complex regional pain syndrome. In another embodiment, the inflammatory pain may be chronic or acute.

[0025] In some embodiments, the dosage forms (e.g., dosage forms containing a triptan (such as rizatriptan or frovatriptan) and / or an NSAID (such as meloxicam)) may be administered to relieve arthritis pain or the signs and / or symptoms of arthritis. Arthritis refers to inflammatory joint disease that may be painful. Examples of arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis (oligoarticular and polyarticular), osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatic), arthropathy, non-articular rheumatism, periarticular disorders, axial spondyloarthritis, simple hip arthritis, vertebral crush fractures, osteoporosis-associated arthritis, and neuropathic arthropathy (such as Charcot foot), axial spondyloarthritis (such as ankylosing spondylitis and SAPHO syndrome). In another embodiment, the arthritis pain may be chronic or acute. In some embodiments, the dosage form may be administered to alleviate the signs and / or symptoms of arthritis (such as, but not limited to, osteoarthritis).

[0026] In some embodiments, the dosage forms (e.g., dosage forms containing a triptan (such as rizatriptan or frovatriptan) and / or an NSAID (such as meloxicam)) may be administered to relieve neuropathic pain (such as diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, sciatica, pudendal neuralgia, and central pain). Other causes of neuropathic pain include, but are not limited to, cancer pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radiation or chemotherapy-associated neuropathy. The neuropathic pain may be chronic or acute.

[0027] For some methods, the dosage form (e.g., a dosage form containing a triptan (such as rizatriptan or frovatriptan) and / or an NSAID (such as meloxicam)) may be administered to relieve musculoskeletal pain. Examples of musculoskeletal pain include, but are not limited to, back pain, lower back pain (e.g., lumbosacral pain), neck pain, infection, cramps, tendonitis, lateral epicondylitis, carpal tunnel syndrome, joint pain, fibromyalgia, injury pain, tunnel syndrome, fracture pain, sprains, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis, and transient femoral neck osteoporosis. In other embodiments, the musculoskeletal pain may be chronic or acute.

[0028] For some methods, administration of the dosage form (e.g., a dosage form containing a triptan (such as rizatriptan or frovatriptan) and / or an NSAID (such as meloxicam)) may achieve suppression of pain that lasts for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, from about 8 hours to about 24 hours, or about 24 hours. In other embodiments, administration of the dosage form may achieve suppression of pain that is observed at about 10 minutes, at about 30 minutes, at about 1 hour, at about 2 hours, at about 3 hours, at about 4 hours, at about 5 hours, at about 6 hours, within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes, within 2 hours, within 3 hours, or other time periods bounded by these ranges after administration of the dosage form.

[0029] A human being treated for a disease or disorder with any of the dosage forms described herein (e.g., dosage forms containing a triptan (e.g., rizatriptan or frovatriptan) and / or an NSAID (e.g., meloxicam)) can be of any age. For example, such a person can be about 10-90 years old, about 20-80 years old, about 30-75 years old, about 40-70 years old, about 1-16 years old, about 80-95 years old, about 18 years old or older, about 20 years old or older, about 25 years old or older, about 30 years old or older, about 40 years old or older, about 45 years old or older, about 50 years old or older, about 55 years old or older, about 60 years old or older, about 65 years old or older, or any other age bounded by or within a range between any of these values.

[0030] In some embodiments, a human being treated for a disease or disorder with a dosage form (e.g., a dosage form containing a triptan (such as rizatriptan or frovatriptan) and / or an NSAID (such as meloxicam)) is a human being who has suffered from pain or a pain-related condition for at least 1 day, at least 1 week, at least 2 weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 6 months, at least 1 year, at least 5 years, at least 10 years, at least 15 years, at least 20 years, at least 30 years, at least 40 years, at least 50 years, or any period bounded by or within a range between any of these values.

[0031] Cyclodextrins used in dosage forms containing drugs (such as meloxicam or other NSAIDs, rizatriptan, frovatriptan, or other triptans) can include cyclodextrins, cyclodextrin derivatives, and / or salts thereof. Cyclodextrins (also known as cycloamylose) are generally cyclic polysaccharides that form a bucket-like shape. Cyclodextrins are hydrophobic on the inside and hydrophilic on the outside, which helps facilitate the transport of hydrophobic molecules into hydrophilic media, thus helping to increase the bioavailability of other molecules. Naturally occurring cyclodextrins include 6, 7, and 8 glucose units (α, β, and γ-cyclodextrins, respectively). However, synthetic cyclodextrins containing more or fewer glucose units are possible. In aqueous solutions, cyclodextrins are known to aggregate around drugs in micellar-type structures, but they can also form complexes (i.e., inclusion complexes) with drugs by incorporating them into the central / hydrophobic part of the cyclodextrin ring. This ability allows cyclodextrins to act as carriers for less water-soluble drugs, increasing their bioavailability.

[0032] The inclusion complex of a drug (such as meloxicam or other NSAIDs, rizatriptan, frovatriptan, or other triptans) with a cyclodextrin may be more water soluble than the uncomplexed drug. The cyclodextrin may be a naturally occurring cyclodextrin (e.g., α-, β-, or γ-cyclodextrin) or a synthetic cyclodextrin. In some embodiments, α-cyclodextrin, its derivatives, or its salts may be used. Examples of α-cyclodextrins include, but are not limited to, (2,3,6-tri-O-acetyl)-α-cyclodextrin, (2,3,6-tri-O-methyl)-α-cyclodextrin, (2,3,6-tri-O-octyl)-α-cyclodextrin, 6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin, (6-O-tertbutyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin, succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, or combinations thereof.

[0033] In some embodiments, β-cyclodextrin, its derivatives, or its salts may be used, including, but not limited to, hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, 6-O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, 6-azido-6-deoxy-β-cyclodextrin, (2,3-diamino-β-cyclodextrin, 6- ... -O-acetyl-6-O-sulfo)-β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD), (2,3-di-O-methyl-6-O-sulfo)-β-cyclodextrin, (2,6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin, (2,3,6-tri-O-methyl)-β-cyclodextrin Dextrin, (2,3,6-tri-O-acetyl)-β-cyclodextrin, -(2,3,6-tri-O-benzoyl)-β-cyclodextrin, (2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-β-cyclodextrin, 6-bromo-6-deoxy-β-cyclodextrin, monoacetyl-β-cyclodextrin, xylose, diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin, (3-O-acetyl-2,6-di-O-methyl)-β-cyclodextrin, (6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin, (6-Ot-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin, succinyl-(2-hydroxypropyl)-β-cyclodextrin, (2,Examples of the cyclodextrin include 6-di-O-ethyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin (CMEβCD), hydroxyethyl-β-cyclodextrin (HEβCD), (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin (HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD), (2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-β-cyclodextrin, methyl-β-cyclodextrin, silyl ((6-O-tert-butyldimethyl)-2,3,-di-O-acetyl)-β-cyclodextrin, succinyl-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, randomly methylated-β-cyclodextrin, branched-β-cyclodextrin, and combinations thereof. ,

[0034] In another embodiment, the β-cyclodextrin may be a sulfoalkyl ether cyclodextrin, a derivative thereof, or a salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives include, but are not limited to, sulfobutyl ether-β-cyclodextrin (e.g., SBEβCD, Betadex, CAPTISOL®). In some embodiments, the SBEβCD may have about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

[0035] In some embodiments, gamma-cyclodextrin, its derivatives, or its salts may be used. Examples of gamma-cyclodextrins include carboxymethyl-gamma-cyclodextrin, (2,3,6-tri-O-acetyl)-gamma-cyclodextrin, (2,3,6-tri-O-methyl)-gamma-cyclodextrin, (2,6-di-O-pentyl)-gamma-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-gamma-cyclodextrin, 6-bromo-6-deoxy-gamma-cyclodextrin, 6-iodo-6-deoxy-gamma-cyclodextrin, (6-Ot-butyldimethylsilyl)-gamma-cyclodextrin, succinyl-gamma-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, (2-hydroxypropyl)-gamma-cyclodextrin, acetyl-gamma-cyclodextrin, butyl-gamma-cyclodextrin, or combinations thereof.

[0036] In some embodiments, the dosage form may include a bicarbonate (such as sodium bicarbonate, potassium bicarbonate, etc.), which may help increase the pharmacokinetics or bioavailability of meloxicam or other drugs (such as rizatriptan).

[0037] In some embodiments, enhanced bioavailability of a drug (such as meloxicam or a triptan (e.g., rizatriptan)) in the present dosage forms may be achieved by administering a dosage form containing a salt form of the drug, forming an inclusion complex of the drug with a cyclodextrin, and / or including a bicarbonate, which may allow for a reduced molar amount of the drug to be used in the treatment of a disease or disorder compared to other dosage forms containing the drug.

[0038] Unless otherwise specified, any reference to a compound described herein (such as meloxicam, an NSAID, a triptan, a rizatriptan, or a cyclodextrin) by structure, name, or any other means, includes pharma- ceutically acceptable salts, alternative solid forms (such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms, etc.), or any other chemical species (precursors, prodrugs), or any other chemical species that may be rapidly converted to a compound described herein under the conditions of using the compounds as described herein.

[0039] In some embodiments, the use of a cyclodextrin or bicarbonate increases the oral bioavailability (e.g., higher C max and / or higher AUC) compared to administration of meloxicam alone may be improved by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at most about 100%, at most about 200%, or any amount within a range bounded by or between any of these values.

[0040] In some embodiments, the use of a cyclodextrin or bicarbonate increases the oral bioavailability (e.g., higher C max and / or higher AUC) compared to administration of the triptan alone may be improved by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at most about 100%, at most about 200%, or any amount bounded by or within a range between any of these values.

[0041] Due to the improved bioavailability as described above, the dosage form may contain, or a subject may be administered, on a molar basis, less of the drug, such as a triptan (e.g., rizatriptan or frovatriptan) or an NSAID (e.g., meloxicam), than would be administered alone. For example, the dosage form may contain, or a mammal may be administered, at least about 10 molar%, at least about 20 molar%, at least about 30 molar%, at least about 40 molar%, at least about 50 molar%, at least about 60 molar%, at least about 70 molar%, at least about 80 molar%, at least about 85 molar%, and / or at most about 90 molar%, 95 molar%, 98 molar% less meloxicam than would be administered alone, or any amount within the range bounded by or between any of these values.

[0042] In another embodiment, when a drug (such as a triptan (e.g., rizatriptan) or an NSAID (e.g., meloxicam)) is administered with a cyclodextrin and / or a bicarbonate, the use of other NSAIDs, opioids, or other analgesics may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, at most about 100%, or any amount within a range bounded by or between any of these values, compared to administration of the NSAID, opioid, or other analgesic alone.

[0043] In some embodiments, the dosage form comprises an NSAID (celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered an NSAID for purposes of this disclosure), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, pinoxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, phenylbutazone, etc.) in an amount of about 1-20 mg / kg. 1000mg, about 1-500mg, about 1-400mg, about 1-300mg, about 1-200mg, about 1-100mg, about 1-50mg, about 1-10mg, about 1-5mg, about 2-6mg, about 3-7m g, about 4-8mg, about 5-10mg, about 7-12mg, about 5-15mg, about 10-20mg, about 15-25mg, about 20-30mg, about 25-35mg, about 30-40mg, about 35-45mg, about It may be included in an amount of about 40-50 mg, about 50-150 mg, about 50-100 mg, about 100-200 mg, about 150-250 mg, about 200-300 mg, about 250-350 mg, about 300-400 mg, about 350-450 mg, about 400-500 mg, about 100 mg, about 200 mg, about 325 mg, or any amount bounded by or within a range between any of these values. These doses may be safe doses for repeated administration (such as repeated administrations 1, 2, 3, or 4 times per day, or repeated administrations repeated at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, about 1 week, about 4 weeks, about 6 weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, about 2 years, etc.).

[0044] In some embodiments, the dosage form may contain meloxicam in an amount of about 1-50 mg, about 1-10 mg, about 1-5 mg, about 10-40 mg, about 1-35 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 7-12 mg, about 5-15 mg, about 10-20 mg, about 10-30 mg, about 18-22 mg, about 19-21 mg, about 15-25 mg, about 20-30 mg, about 25-35 mg, about 30-40 mg, about 35-45 mg, about 40-50 mg, about 1-25 mg, about 1-15 mg, about 5-20 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, or any amount within a range bounded by or between any of these values. For the amounts of meloxicam (or any other compound) described herein, a salt form of meloxicam (or other compound) may be present in the amounts described above or in an amount that is the molar equivalent of such amount for the non-salt form of meloxicam (or other compound). These doses may be safe doses for repeated administration (such as repeated administrations 1, 2, 3, or 4 times per day, or repeated administrations repeated at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, about 1-2 months, about 4 weeks, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, about 2 years, etc.).

[0045] For some dosage forms, the drug (such as meloxicam, frovatriptan, or rizatriptan) forms a complex with a substituted-β-cyclodextrin or other cyclodextrin that can be formulated into a solid dosage form. Such dosage forms may be suitable for oral administration. Alternatively, the drug-cyclodextrin inclusion complex may be dissolved in water or other solvent to form a parenteral formulation. However, a physical mixture of the drug and the substituted-β-cyclodextrin or other cyclodextrin that is not an inclusion complex may be used in an oral or parenteral dosage form.

[0046] The formation of inclusion complexes between drugs (such as meloxicam, frovatriptan, or rizatriptan) and cyclodextrins can help improve the properties of the dosage form. For some inclusion complexes, the drug and cyclodextrin (e.g., SBEβCD) may have a molar ratio of about 0.5-2, about 0.5-0.7, about 0.6-0.8, about 0.7-0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3, about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 1.9-2.1, about 2-2.2, about 0.8-1.2, about 1 (a molar ratio of 0.5 is 0.5 moles of drug to 1 mole of cyclodextrin), or any ratio within a range bounded by any of these values.

[0047] In some embodiments, the inclusion complex is formed by (1) mixing a homogeneous solution of the drug (such as meloxicam or triptan) with a homogeneous solution of cyclodextrin to form a homogeneous solution of the drug and cyclodextrin, and (2) removing or evaporating the solvent from the homogeneous solution of the drug and cyclodextrin to form a complex comprising an inclusion complex of the drug within the cyclodextrin. In some embodiments, these solutions can be pH-adjusted aqueous solutions. The pH can be adjusted using a buffering agent. In some embodiments, the solvent can be removed or evaporated by freeze drying, spray drying, or other suitable means. In some embodiments, the solvent can be removed by vacuum drying, or the like.

[0048] For some dosage forms, the cyclodextrin (e.g., SBEβCD) may be employed in a weight ratio to meloxicam within the ranges of about 1-1000, about 1-500, about 1-5, about 1-20, about 1-10, about 1-15, about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, about 0.01-1, about 0.05-1, about 0.1-1, about 0.2-1, about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1 (e.g., 1 gram of cyclodextrin per 1 gram of meloxicam would be a weight ratio of 1), or any weight ratio within the ranges bounded by or between any of these values. Each type of cyclodextrin employed may have different weight ratios to meloxicam in the dosage form.

[0049] For some dosage forms, the cyclodextrin (e.g., SBEβCD) is at about 1-1000, about 1-500, about 1-100, about 1-50, about 1-20, about 1-10, about 1-15, about 1-5, about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, about 0.01-1, about 0.05- cyclodextrin may be employed in a weight ratio within the range of about 1, about 0.1-1, about 0.2-1, about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1 (e.g., 10 grams of cyclodextrin per gram of rizatriptan or frovatriptan would be a weight ratio of 10), or any weight ratio within the range bounded by or between any of these values. Each type of cyclodextrin employed may have a different weight ratio to the triptan in the dosage form.

[0050] For some dosage forms, the cyclodextrin (e.g., SBEβCD) may be present in an amount of about 1-1000, about 1-500, about 1-100, about 1-50, about 1-20, about 1-10, about 1-15, about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, about 9-11, about 10-12, about 11-13, about 12-14, about 13-15, about 14-16, about 15-17, about 16-18, about 17-19, about 18-20, about 20-22, about 22-24, about 24-26, about 26-28, about 28-29, about 30-31, about 31-32, about 32-33, about 33-34, about 34-35, about 35-36, about 36-37, about 37-38, about 38-39, about 40-41, about 42-43, about 44-45, about 46-46, about 48-47, about 49-50, about 50-51, about 52-53, about 54-55, about 56-57, about 58-59, about 59-60, about 60-61, about 61-62, about 62-63, about 63-64, about 64-65, about 65-66, about 66-67, about 67-68, about 68-70, about 69-81, about 71-72, about 73-74, about 7 -20, about 19-21, about 0.001-1, about 0.01-1, about 0.05-1, about 0.1-1, about 0.2-1, about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1 (e.g., 10 grams of cyclodextrin per gram of rizatriptan would be a weight ratio of 10), or any weight ratio within or between any of these values. Each type of cyclodextrin employed may have a different weight ratio to rizatriptan in the dosage form.

[0051] In some embodiments, the dosage form contains about 1-50 mg, about 1-10 mg, about 20-30 mg, about 30-40 mg, or about 40-50 mg, about 10-40 mg, about 1-35 mg, about 1-25 mg, about 1-15 mg, about 1-10 mg, about 5-20 mg, about 1-50 mg, about 1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-11 mg, about 9-14 mg, about 10-15 mg, about 11-16 mg, about The compound may be present in an amount of about 12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20 mg, about 5-15 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 10 mg, about 15 mg, about 30 mg, or any amount within a range bounded by or between any of these values.

[0052] For any amount of rizatriptan described herein, salt forms of rizatriptan may be present in the amounts described above or in amounts that are the molar equivalents of these amounts for rizatriptan free base.For example, when the molecular weight of rizatriptan free base is 269.3 g / mol, 10 mg of rizatriptan is equivalent to 37.1 mmol of rizatriptan.Thus, the molar equivalent of 10 mg of rizatriptan free base is the mass of 37.1 mmol of salt form.For example, for the benzoate salt (mw=391.2 g / mol), the molar equivalent of 10 mg (or 37.1 mmol) of free base is 14.5 mg. These doses may be safe doses for repeated administration (such as repeated administrations 1, 2, 3, or 4 times per day, or repeated administrations repeated at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, etc.).

[0053] The other triptan may be administered to the patient in any dose that is effective for analgesia, in some embodiments, the dosage form may contain the triptan in any amount bounded by or within the range between any of the values ​​recited above.

[0054] In some embodiments, the dosage form comprises about 1-50 mg, about 1-10 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 10-40 mg, about 1-35 mg, about 1-25 mg, about 1-15 mg, about 5-20 mg, about 1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-11 mg, about 9-14 mg, about 10-15 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 ... It may be included in an amount of about 1-16 mg, about 12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20 mg, about 5-15 mg, about 10-20 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 10 mg, about 15 mg, about 30 mg, or any amount within or between any of these bounds. These doses may be safe doses for repeated administration (such as repeated administrations 1, 2, 3, or 4 times per day, or repeated administrations repeated at intervals of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, about 4 weeks, about 4-6 weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, about 2 years, etc.).

[0055] For some dosage forms, the cyclodextrin (e.g., SBEβCD) may be administered in the amount of about 1-200 mg, about 1-100 mg, 25-175 mg, about 50-150 mg, about 50-100 mg, about 50-200 mg, about 25-100 mg, about 75-150 mg, about 100-175 mg, about 20-80 mg, about 25-50 mg, about 60-100 mg, about 80-100 mg, about 100 mg, about 80-120 mg, or about 100 mg. mg, about 100-120 mg, about 100-140 mg, about 120-160 mg, about 140-180 mg, about 150-200 mg, about 100-150 mg, about 30-90 mg, about 40-60 mg, about 40-80 mg, about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amount within the range bounded by or between any of these values.

[0056] For some dosage forms, the inclusion complex of the drug (such as meloxicam or other NSAID, or rizatriptan, frovatriptan, or other triptan) with cyclodextrin is about 1-10%, 5-20%, 5-15%, 6-16%, 7-17%, 8-18%, 9-19%, 10-20%, 15-30%, 30-40%, 40-50%, 50-70%, or 70-90% based on the total weight of the dosage form, or any percentage within a range bounded by any of these values.

[0057] Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) in an amount of about 1-2000 mg, about 1-1000 mg, about 100-1000 mg, about 200-800 mg, about 1-500 mg, about 1-200 mg, about 1-100 mg, about 50-750 mg, about 500-1000 mg, about 100-500 mg, about 100-300 mg, about 500-1000 mg, about 300-700 mg, about 400-600 mg, about 50-250 mg, about 50-100 mg, about 250-750 mg, about 100-200 mg, about 200-300 mg, about 300-400 mg, about 400-500 mg, about 41 The compound may be present in an amount of about 0-510 mg, about 420-520 mg, about 430-530 mg, about 440-540 mg, about 450-550 mg, about 460-560 mg, about 470-570 mg, about 480-580 mg, about 490-590 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 900-1000 mg, about 150-650 mg, about 350-850 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or any amount within a range bounded by or between any of these values.

[0058] The bicarbonate (e.g., sodium bicarbonate) may be at least about 10%, at least about 15%, at least about 20%, about 20-40%, about 30-50%, about 40-60%, about 50-70%, about 60-80%, or about 70-90% based on the total weight of the dosage form, or any percentage within a range bounded by any of these values.

[0059] In some embodiments, the daily dose of meloxicam, or the amount of meloxicam administered per day (either in a single dose or in two or more divided doses totaling the daily dose), is about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-28 mg, about 2-29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about mg, about 2-27mg, about 2-28mg, about 2-29mg, about 2-30mg, about 2-35mg, about 2-40mg, about 2-45mg, about 2-50mg, about 2-55mg, about 2-60mg, about 2-65mg, about 2-70mg, about 2-75mg, about 3-8mg, about 4-9mg, about 5- 10mg, about 6-11mg, about 7-12mg, about 8-13mg, about 9-14mg, about 10-15mg, about 11-16mg, about 12-17mg, about 13-18mg, about 14-19mg, about 15-20mg, about 16-21mg, about 17-22mg, about 18-23mg, about 19-24 mg, about 20-25mg, about 21-26mg, about 22-27mg, about 23-28mg, about 24-29mg, about 25-30mg, about 26-31mg, about 27-32mg, about 28-33mg, about 29-34mg, about 30-35mg, about 31-36mg, about 32-37mg, about 33- 38mg, about 34-39mg, about 35-40mg, about 36-41mg, about 37-42mg, about 38-43mg, about 39-44mg, about 40-45mg, about 41-46mg, about 42-47mg, about 43-48mg, about 44-49mg, about 45-50mg, about 46-51mg, about 4 7-52mg, about 48-53mg, about 49-54mg, about 50-55mg, about 51-56mg, about 52-57mg, about 53-58mg, about 54-59mg, about 55-60mg, about 56-61mg, about 57-62mg, about 58-63mg, about 59-64mg, about 60-65mg, About 61-66mg, about 62-67mg, about 63-68mg, about 64-69mg, about 65-70mg, about 66-71mg, about 67-72mg, about 68-73mg, about 69-74mg, about 70-75mg, about 5-10mg, about 10-15mg, about 15-20mg, about 20-25mg,About 25-30 mg, about 30-35 mg, or any amount within a range bounded by any of these values. The daily dose may be given in a single dose once a day, or in divided doses given two, three, four or more times a day.

[0060] In some embodiments, the weekly dose of meloxicam, or the amount of meloxicam administered per week (either in a single dose or in two or more divided doses totaling the weekly dose), is about 1-1000 mg, about 1-500 mg, about 10-250 mg, about 100-300 mg, about 10-100 mg, about 10-150 mg, about 10-300 mg, about 20-150 mg, about 20-60 mg, about 30- 70mg, about 40-60mg, about 50-70mg, about 70-90mg, about 90-110mg, about 80-450mg, about 80-100mg, about 90-110mg, about 100-120mg, about 110 -130mg, about 120-140mg, about 130-150mg, about 140-160mg, about 150-170mg, about 160-180mg, about 170-190mg, about 180-200mg, about 19 0-210mg, about 200-220mg, about 210-230mg, about 220-240mg, about 230-250mg, about 240-260mg, about 250-270mg, about 260-280mg, about 2 70-290mg, about 280-300mg, about 290-310mg, about 300-320mg, about 310-330mg, about 320-340mg, about 330-350mg, about 340-360mg, about 350-370 mg, about 360-380 mg, about 370-390 mg, about 380-400 mg, about 390-410 mg, about 400-420 mg, about 410-430 mg, about 420-440 mg, about 430-450 mg, about 50 mg, about 55 mg, about 100-150 mg, about 30-100 mg, or any amount within a range bounded by or between any of these values. The weekly dose may be given in a single administration once per week, or in two, three, four, five, six, or seven separate administrations during the week.

[0061] In some embodiments, the monthly dose (e.g., oral dose) of meloxicam, or the dose administered over a monthly period, is about 5000 mg or less, about 4000 mg or less, about 3000 mg or less, about 2000 mg or less, about 1000 mg or less, about 700 mg or less, about 600 mg or less, about 300-2400 mg, about 300-350 mg, about 310-360 mg, about 320-370 mg, about 330-380 mg, about 340-390 mg, about 350-400 mg, about 360-410 mg, about 370-420 mg, about 380-430 mg, about 390-440 mg, about 400- 450mg, about 410-460mg, about 420-470mg, about 430-480mg, about 440-490mg, about 450-500mg, about 460-510mg, about 470-520mg, about 480-530mg, about 490-540mg, about 500-550mg, about 510-560mg, about 520-570mg, about 530-580mg, about 540-590mg, about 550-600mg, about 560-610mg, about 570-620mg, about 580-630mg, about 590-640mg, about 600-650mg, about 610-660mg, about 620-670mg, about 6 30-680mg, about 640-690mg, about 650-700mg, about 660-710mg, about 670-720mg, about 680-730mg, about 690-740mg, about 700-750mg, about 710-760mg, about 720-770mg, about 730-780mg, about 740-7 90mg, about 750-800mg, about 760-810mg, about 770-820mg, about 780-830mg, about 790-840mg, about 800-850mg, about 810-860mg, about 820-870mg, about 830-880mg, about 840-890mg, about 850-900mg , about 860-910mg, about 870-920mg, about 880-930mg, about 890-940mg, about 900-950mg, about 910-960mg, about 920-970mg, about 930-980mg, about 940-990mg, about 950-1000mg, about 960-1010mg, about 970-1020mg, about 980-1030mg, about 990-1040mg, about 1000-1050mg, about 1010-1060mg, about 1020-1070mg, about 1030-1080mg, about 1040-1090mg, about 1050-1100mg, about 1060-1110mg,About 1070 - 1120 mg, about 1080 - 1130 mg, about 1090 - 1140 mg, about 1100 - 1150 mg, about 1110 - 1160 mg, about 1120 - 1170 mg, about 1130 - 1180 mg, about 1140 - 1190 mg, about 1150 - 1200 mg, about 1160 - 1210 mg, about 1170 - 1220 mg, about 1180 - 1230 mg, about 1190 - 1240 mg, about 1200 - 1250 mg, about 1210 - 1260 mg, about 1220 - 1270 mg, about 1230 - 1280 mg, about 1240 - 1290 mg, about 1250 - 1300 mg, about 1260 - 1310 mg, about 1270 - 1320 mg, about 1280 - 1330 mg, about 1290 - 1340 mg, about 1300 - 1350 mg, about 1310 - 1360 mg, about 1320 - 1370 mg, about 1330 - 1380 mg, about 1340 - 1390 mg, about 1350 - 1400 mg, about 1360 - 1410 mg, about 1370 - 1420 mg, about 1380 - 1430 mg, about 1390 - 1440 mg, about 1400 - 1450 mg, about 1410 - 1460 mg, about 1420 - 1470 mg, about 1430 - 1480 mg, about 1440 - 1490 mg, about 1450 - 1500 mg, about 1460 - 1510 mg, about 1470 - 1520 mg, about 1480 - 1530 mg, about 1490 - 1540 mg, about 1500 - 1550 mg, about 1510 - 1560 mg, about 1520 - 1570 mg, about 1530 - 1580 mg, about 1540 - 1590 mg, about 1550 - 1600 mg, about 1560 - 1610 mg, about 1570 - 1620 mg, about 1580 - 1630 mg, about 1590 - 1640 mg, about 1600 - 1650 mg, about 1610 - 1660 mg, about 1620 - 1670 mg, about 1630 - 1680 mg, about 1640 - 1690 mg, about 1650 - 1700 mg, about 1660 - 1710 mg, about 1670 - 1720 mg, about 1680 - 1730 mg, about 1690 - 1740 mg, about 1700 - 1750 mg, about 1710 - 1760 mg, about 1720 - 1770 mg, about 1730 - 1780 mg, about 1740 - 1790 mg, about 1750 - 1800 mg, about 1760 - 1810 mg, about 1770 - 1820 mg, about 1780 - 1830 mg, about 1790 - 1840 mg, about 1800 - 1850 mg, about 1810 - 1860 mg, about 1820 - 1870 mg, about 1830 - 1880 mgAbout 1840-1890mg, about 1850-1900mg, about 1860-1910mg, about 1870-1920mg, about 1880-1930mg, about 1890-1940mg, about 1900-1950mg, about 1910-1960mg, about 1920-1970mg, about 1 930-1980mg, about 1940-1990mg, about 1950-2000mg, about 1960-2010mg, about 1970-2020mg, about 1980-2030mg, about 1990-2040mg, about 2000-2050mg, about 2010-2060mg, about 2020 -2070mg, about 2030-2080mg, about 2040-2090mg, about 2050-2100mg, about 2060-2110mg, about 2070-2120mg, about 2080-2130mg, about 2090-2140mg, about 2100-2150mg, about 2110-21 60mg, about 2120-2170mg, about 2130-2180mg, about 2140-2190mg, about 2150-2200mg, about 2160-2210mg, about 2170-2220mg, about 2180-2230mg, about 2190-2240mg, about 2200-2250m g, about 2210-2260mg, about 2220-2270mg, about 2230-2280mg, about 2240-2290mg, about 2250-2300mg, about 2260-2310mg, about 2270-2320mg, about 2280-2330mg, about 2290-2340mg, About 2300-2350mg, about 2310-2360mg, about 2320-2370mg, about 2330-2380mg, about 2340-2390mg, about 2350-2400mg, about 1-4000mg, about 1-1000mg, about 10-1000mg, about 50-1000mg, about 10-600mg, about 40-600mg, about 50-600mg, about 40-400mg, about 50-200mg, about 200-240mg, about 240-280mg, about 280-320mg, about 320-360mg, about 360-400mg, about 400-450mg, about 450-500mg, about 500-600mg, about 250-350mg, about 100-600mg, about 40-2000mg, about 40-800mg, about 100-900mg, about 100-800mg, about 40-1000mg, about 50-1000mg, about 100-1000mg, orAny of these values ​​are bounded by or within the range between any of the monthly doses. The monthly dose may be given in a single dose or as two or more separate doses administered over a period of time. In some embodiments, the monthly dose is administered every other week in two or three divided doses. In some embodiments, the monthly dose is administered every week in four or five divided doses. In some embodiments, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses, or more divided doses. In some embodiments, the monthly dose is administered in 5 to 15 divided doses over a period of time. The monthly dose may be administered for only one month, or may be administered repeatedly over two, three, four, five, six, or more months.

[0062] In some embodiments, the daily dose (e.g., oral dose, parenteral dose, etc.) of frovatriptan or other triptan is about 0.5-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-31 mg, about 2-32 mg, about 2-33 mg, about 2-34 mg, about 2-35 mg, about 2-36 mg, about 2-37 mg, about 2-38 mg, about 2-39 mg, about 2-40 mg, about 2-41 mg, about 2-42 mg, about 2-43 mg, about 2-44 mg, about 2-45 mg, about 2-46 mg, about 2-47 mg, about 2-48 mg, about 2-49 mg, about 2-50 mg, about 2-51 mg, about 2-52 mg, about 2-53 mg, about 2-54 mg, about 2-55 mg, about 2-56 mg, about 2-57 mg, about 2-58 mg, about 2-59 mg, about 2-60 mg, about 2-61 mg, about 2 19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or any amount within a range bounded by any of these values.

[0063] In some embodiments, the daily dose of rizatriptan is about 0.5-100 mg, about 5-50 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 1-5 mg, about 1-6 mg, about 2-7 mg, about 3-8 mg, about 4-9 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about 11-16 mg, about 12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20 mg, about 16-21 mg, about 17-22 mg, about 18-23 mg, about 19-24 mg, about 20-25 mg, about 21-26 mg, about 22-27 mg, about 23-28 mg, about 24-29 mg, about 25-30 mg, about 26-31 mg, about 27-32 mg, about 28-33 mg, about 29-34 mg, about 30-35 mg, about 31-36 mg, about 32-37 mg, about 33-38 mg, about 34-39 mg, about 35-40 mg, about 36-41 mg, about 37-42 mg, about 38-43 mg, about 39-44 mg, about 40-45 mg, about 41-46 mg, about 42-47 mg, about 43-48 mg, about 44-49 mg, about 45-50 mg, about 46-51 mg, about 47-52 mg, 48-53 mg, about 49-54 mg, about 50-55 mg, or any amount within a range bounded by any of these values. The daily dose may be given in a single dose, once daily, or in divided doses, two, three, four or more times daily.

[0064] In some embodiments, the weekly dose (e.g., oral dose) of frovatriptan or other triptan is about 1-1000 mg, about 1-500 mg, about 10-250 mg, about 100-300 mg, about 10-100 mg, about 10-150 mg, about 10-300 mg, about 20-150 mg, about 20-60 mg, about 30-70 mg, about 40-60 mg, about 50-70 mg, about 70-90 mg, about 90-110 mg, about 50 mg, about 55 mg, about 100-150 mg, about 30-100 mg, about 1-20 mg, about 1-10 mg, about 2-10 mg, about 2-5 mg, about 5-10 mg, about 2.5 mg, about 5 mg, about 7.5 mg, or any amount within a range bounded by or between any of these values. The weekly dose may be given in a single administration once a week, or in two, three, four, five, six, or seven separate administrations during the week.

[0065] In some embodiments, the weekly dose of rizatriptan is about 1-1000 mg, about 10-400 mg, about 50-250 mg, about 1-500 mg, about 10-250 mg, about 100-300 mg, about 10-100 mg, about 10-150 mg, about 10-300 mg, about 20-150 mg, about 20-60 mg, about 30-70 mg, about 40-60 mg, about 50-70 mg, about 70-90 mg , about 90-110mg, about 50mg, about 55mg, about 100-150mg, about 30-100mg, about 1-20mg, about 1-10mg, about 2-10mg, about 2-5mg, about 5-10mg, about 1-50mg, about 10-60mg, about 20-70mg, about 30-80mg, about 40-90mg, about 50-100mg, about 60-110mg, about 70-120mg, about 80-130mg, about 9 0-140mg, about 100-150mg, about 110-160mg, about 120-170mg, about 130-180mg, about 140-190mg, about 150-200mg, about 160-210mg , about 170-220mg, about 180-230mg, about 190-240mg, about 200-250mg, about 210-260mg, about 220-270mg, about 230-280mg, about 240-2 90 mg, about 250-300 mg, about 260-310 mg, about 270-320 mg, about 280-330 mg, about 290-340 mg, about 300-350 mg, about 310-360 mg, about 320-370 mg, about 330-380 mg, about 340-390 mg, about 350-400 mg, or any amount within a range bounded by or between any of these values. The weekly dose may be given in a single administration once per week, or in two, three, four, five, six, or seven separate administrations during the week.

[0066] In some embodiments, the monthly dose (e.g., oral dose) of frovatriptan or other triptan, or the dose administered over a monthly period, is about 5000 mg or less, about 4000 mg or less, about 3000 mg or less, about 2000 mg or less, about 1000 mg or less, about 700 mg or less, about 600 mg or less, about 1-4000 mg, about 1-1000 mg, about 10-1000 mg, about 50-1000 mg, about 10-600 mg, about 40-600 mg, about 50-600 mg, about 40-400 mg, about 50-200 mg, about 200-240 mg, about 240- 280mg, about 280-320mg, about 320-360mg, about 360-400mg, about 400-450mg, about 450-500mg, about 500-600mg, about 250-350mg, about 100-600mg, about 40-2000mg, about 40-800mg, about 100-900mg, about 100-800mg, about 40-1000mg, about 50-1000mg, about 100-1000mg, about 10-80mg, about 10-40mg, about 20-30mg, or any monthly dose bounded by or within any of these values. The monthly dose may be given in a single dose or as two or more separate doses administered monthly. In some embodiments, the monthly dose is administered every other week in two or three divided doses. In some embodiments, the monthly dose is administered weekly in 4 or 5 divided doses. In some embodiments, the monthly dose is administered daily in 28 to 31 divided doses, or in 56 to 62 divided doses, or more. In some embodiments, the monthly dose is administered in 5 to 15 divided doses per month. The monthly dose may be administered for only one month, or may be administered repeatedly over 2, 3, 4, 5, 6, or more months.

[0067] In some embodiments, the monthly dose of rizatriptan, or the total dose administered within a month period, is about 5000 mg or less, about 4000 mg or less, about 3000 mg or less, about 2000 mg or less, about 1000 mg or less, about 700 mg or less, about 600 mg or less, about 1-4000 mg, about 1-1000 mg, about 10-1000 mg, about 50-1000 mg, about 10-600 mg, about 40-600 mg, about 50-600 mg, about 150-2400 mg, about 150-200 mg, about 160-210 mg, about 170-220 mg, about 180-230 mg, about 190-240 mg, or about 200-250 mg. g, about 200-250mg, about 210-260mg, about 220-270mg, about 230-280mg, about 240-290mg, about 250-300mg, about 260-310mg, about 270-320mg, about 280-330mg, about 290-340mg, about 300-350mg, about 3 10-360mg, about 320-370mg, about 330-380mg, about 340-390mg, about 350-400mg, about 360-410mg, about 370-420mg, about 380-430mg, about 390-440mg, about 400-450mg, about 410-460mg, about 420-4 70mg, about 430-480mg, about 440-490mg, about 450-500mg, about 460-510mg, about 470-520mg, about 480-530mg, about 490-540mg, about 500-550mg, about 510-560mg, about 520-570mg, about 530-580mg , about 540-590mg, about 550-600mg, about 560-610mg, about 570-620mg, about 580-630mg, about 590-640mg, about 600-650mg, about 610-660mg, about 620-670mg, about 630-680mg, about 640-690mg, about 65 0-700mg, about 660-710mg, about 670-720mg, about 680-730mg, about 690-740mg, about 700-750mg, about 710-760mg, about 720-770mg, about 730-780mg, about 740-790mg, about 750-800mg, about 760-81 0mg, about 770-820mg, about 780-830mg, about 790-840mg, about 800-850mg, about 810-860mg, about 820-870mg, about 830-880mg, about 840-890mg, about 850-900mg, about 860-910mg, about 870-920mg,About 880 - 930 mg, about 890 - 940 mg, about 900 - 950 mg, about 910 - 960 mg, about 920 - 970 mg, about 930 - 980 mg, about 940 - 990 mg, about 950 - 1000 mg, about 960 - 1010 mg, about 970 - 1020 mg, about 980 - 1030 mg, about 990 - 1040 mg, about 1000 - 1050 mg, about 1010 - 1060 mg, about 1020 - 1070 mg, about 1030 - 1080 mg, about 1040 - 1090 mg, about 1050 - 1100 mg, about 1060 - 1110 mg, about 1070 - 1120 mg, about 1080 - 1130 mg, about 1090 - 1140 mg, about 1100 - 1150 mg, about 1110 - 1160 mg, about 1120 - 1170 mg, about 1130 - 1180 mg, about 1140 - 1190 mg, about 1150 - 1200 mg, about 1160 - 1210 mg, about 1170 - 1220 mg, about 1180 - 1230 mg, about 1190 - 1240 mg, about 1200 - 1250 mg, about 1210 - 1260 mg, about 1220 - 1270 mg, about 1230 - 1280 mg, about 1240 - 1290 mg, about 1250 - 1300 mg, about 1260 - 1310 mg, about 1270 - 1320 mg, about 1280 - 1330 mg, about 1290 - 1340 mg, about 1300 - 1350 mg, about 1310 - 1360 mg, about 1320 - 1370 mg, about 1330 - 1380 mg, about 1340 - 1390 mg, about 1350 - 1400 mg, about 1360 - 1410 mg, about 1370 - 1420 mg, about 1380 - 1430 mg, about 1390 - 1440 mg, about 1400 - 1450 mg, about 1410 - 1460 mg, about 1420 - 1470 mg, about 1430 - 1480 mg, about 1440 - 1490 mg, about 1450 - 1500 mg, about 1460 - 1510 mg, about 1470 - 1520 mg, about 1480 - 1530 mg, about 1490 - 1540 mg, about 1500 - 1550 mg, about 1510 - 1560 mg, about 1520 - 1570 mg, about 1530 - 1580 mg, about 1540 - 1590 mg, about 1550 - 1600 mg, about 1560 - 1610 mg, about 1570 - 1620 mg, about 1580 - 1630 mg, about 1590 - 1640 mg, about 1600 - 1650 mg, about 1610 - 1660 mg, about 1620 - 1670 mg, about 1630 - 1680 mg, about 1640 - 1690 mg, about 1650 - 1700 mgabout 1660 - 1710 mg, about 1670 - 1720 mg, about 1680 - 1730 mg, about 1690 - 1740 mg, about 1700 - 1750 mg, about 1710 - 1760 mg, about 1720 - 1770 mg, about 1730 - 1780 mg, about 1740 - 1790 mg, about 1750 - 1800 mg, about 1760 - 1810 mg, about 1770 - 1820 mg, about 1780 - 1830 mg, about 1790 - 1840 mg, about 1800 - 1850 mg, about 1810 - 1860 mg, about 1820 - 1870 mg, about 1830 - 1880 mg, about 1840 - 1890 mg, about 1850 - 1900 mg, about 1860 - 1910 mg, about 1870 - 1920 mg, about 1880 - 1930 mg, about 1890 - 1940 mg, about 1900 - 1950 mg, about 1910 - 1960 mg, about 1920 - 1970 mg, about 1930 - 1980 mg, about 1940 - 1990 mg, about 1950 - 2000 mg, about 1960 - 2010 mg, about 1970 - 2020 mg, about 1980 - 2030 mg, about 1990 - 2040 mg, about 2000 - 2050 mg, about 2010 - 2060 mg, about 2020 - 2070 mg, about 2030 - 2080 mg, about 2040 - 2090 mg, about 2050 - 2100 mg, about 2060 - 2110 mg, about 2070 - 2120 mg, about 2080 - 2130 mg, about 2090 - 2140 mg, about 2100 - 2150 mg, about 2110 - 2160 mg, about 2120 - 2170 mg, about 2130 - 2180 mg, about 2140 - 2190 mg, about 2150 - 2200 mg, about 2160 - 2210 mg, about 2170 - 2220 mg, about 2180 - 2230 mg, about 2190 - 2240 mg, about 2200 - 2250 mg, about 2210 - 2260 mg, about 2220 - 2270 mg, about 2230 - 2280 mg, about 2240 - 2290 mg, about 2250 - 2300 mg, about 2260 - 2310 mg, about 2270 - 2320 mg, about 2280 - 2330 mg, about 2290 - 2340 mg, about 2300 - 2350 mg, about 2310 - 2360 mg, about 2320 - 2370 mg, about 2330 - 2380 mg, about 2340 - 2390 mg, about 2350 - 2400 mg, about 40 - 400 mg, about 50 - 200 mg, about 200 - 240 mg, about 240 - 280 mg, about 280 - 320 mg, about 320 - 360 mg, about 360 - 400 mg, about 400 - 450 mgThe monthly dose may be about 450-500 mg, about 500-600 mg, about 250-350 mg, about 100-600 mg, about 40-2000 mg, about 40-800 mg, about 100-900 mg, about 100-800 mg, about 40-1000 mg, about 50-1000 mg, about 100-1000 mg, about 10-80 mg, about 10-40 mg, about 20-30 mg, or any monthly dose bounded by or within any of these values. The monthly dose may be given in a single dose or as two or more separate doses administered monthly. In some embodiments, the monthly dose is administered every other week in two or three divided doses. In some embodiments, the monthly dose is administered every week in four or five divided doses. In some embodiments, the monthly dose is administered in 28 to 31 sub-doses, or in 56 to 62 sub-doses, or more sub-doses, daily. In some embodiments, the monthly dose is administered in 5 to 15 sub-doses per month. The monthly dose may be administered for only one month, or may be administered repeatedly over two, three, four, five, six, or more months.

[0068] In another embodiment, the dosage form may be administered weekly, or every other week or biweekly, or once every three weeks for about 1, 2, 3, 4 or more consecutive weeks. This dosing regimen may be repeated weekly, twice a month, three times a month, monthly, once every two months, once every three months, or as directed by a medical professional.

[0069] In some embodiments, administration of the pharmaceutical compositions may result in, for example, improved pharmacokinetics in fasted human subjects (e.g., increased bioavailability (e.g., decreased T max , increased C max, increased AUC, etc.). In some embodiments, the bioavailability of the drug increases with repeated dosing. For example, the bioavailability of the drug (e.g., meloxicam or other NSAID, rizatriptan, frovatriptan, or other triptan) at this dosage form may be increased, for example, in fasted human subjects, after about 1-10 days after repeated dosing, after about 2-6 days after repeated dosing, after about 3-5 days after repeated dosing, after about 4-6 days after repeated dosing, after about 5-8 days after repeated dosing, after about 5 days after repeated dosing, after about 6 days after repeated dosing, after about 7 days after repeated dosing, after about 8 days after repeated dosing, after about 10 days after repeated dosing, after about 15 days after repeated dosing, or any period bounded by or between any of these values, as compared to the bioavailability of the drug in a dosage form that does not include a cyclodextrin, an antacid, or a buffer (e.g., a bicarbonate). Administration of a drug to a human subject or patient in any of the dosage forms described herein may improve or achieve the desired oral pharmacokinetic properties of the drug.

[0070] T max , C max Any reference to AUC, AUC, or any other pharmacokinetic parameter includes the average, mean, or median in humans (e.g., human patients or human subjects).

[0071] Administration of some of the dosage forms to humans can result in a desired range of meloxicam area under the plasma concentration curve (AUC). For example, the dosage forms containing meloxicam can provide a range of AUCs of about 1-150 μg·hr / mL, about 10-30 μg·hr / mL, about 20-40 μg·hr / mL, about 30-50 μg·hr / mL, about 40-60 μg·hr / mL, about 50-70 μg·hr / mL, about 60-80 μg·hr / mL, about 70-90 μg·hr / mL, about 80-100 μg·hr / mL, about 10-100 μg·hr / mL, about 50-150 μg·hr / mL, about 25-125 μg·hr / mL, about 75-150 μg·hr / mL , about 20-50 μg·hr / mL, about 40-70 μg·hr / mL, about 60-90 μg·hr / mL, about 80-110 μg·hr / mL, about 100-130 μg·hr / mL, about 120-150 μg·hr / mL, about 100-150 μg·hr / mL (e.g., median, mean, or average AUC of meloxicam in humans), or any AUC bounded by or within the ranges between any of these values.

[0072] Administration of some of the dosage forms to humans can result in a desired range of area under the plasma concentration curve (AUC) of frovatriptan. For example, dosage forms containing frovatriptan or other triptans can provide AUCs of about 1-150 μg·hr / mL, about 10-30 μg·hr / mL, about 20-40 μg·hr / mL, about 30-50 μg·hr / mL, about 40-60 μg·hr / mL, about 50-70 μg·hr / mL, about 60-80 μg·hr / mL, about 70-90 μg·hr / mL, about 80-100 μg·hr / mL, about 10-100 μg·hr / mL, about 50-150 μg·hr / mL, about 25-125 μg·hr / mL, about 75-150 μg·hr / mL, about 80-150 μg·hr / mL, about 100-150 μg·hr / mL, about 25-125 μg·hr / mL, about 30-350 μg·hr / mL, about 35-400 μg·hr / mL, about 40-60 μg·hr / mL, about 50-70 μg·hr / mL, about 60-80 μg·hr / mL, about 70-90 μg·hr / mL, about 80-100 μg·hr / mL, about 100-150 μg·hr / mL, about 50-150 μg·hr / mL, about 25-125 μg·hr / mL, about 35-400 μg·hr / mL, about 40-60 μg·hr / mL, about 50-70 μg·hr / mL, about 60-80 μg·hr / mL, about 70-90 μg·hr / mL, about 80- The AUC may be about 20-50 μg·hr / mL, about 40-70 μg·hr / mL, about 60-90 μg·hr / mL, about 80-110 μg·hr / mL, about 100-130 μg·hr / mL, about 120-150 μg·hr / mL, or any AUC within the range between or bounded by any of these values.

[0073] Unless otherwise stated, AUC is the AUC calculated up to the final measured concentration (AUC 0-t ), AUC calculated over a 24-h period (AUC 0-24 ), or AUC extrapolated to infinite time (AUC 0-inf )

[0074] For several acute pain disorders (such as migraine and other types of headache), the short-term AUC (AUC measured over 6 hours or AUC 0-6 ), which may be of particular interest, for example, for rapid analgesia. For example, some dosage forms have an AUC of meloxicam of at least about 6 μg·h / mL (or 6,000 ng·h / mL), at least about 7 μg·h / mL (or 7,000 ng·h / mL), at least about 8 μg·h / mL (or 8,000 ng·h / mL), at least about 9 μg·h / mL (or 9,000 ng·h / mL), about 6-10 μg·h / mL, about 7-11 μg·h / mL, about 8-12 μg·h / mL, about 9-13 μg·h / mL. 0-6 (Mean, Mean, or Average AUC of Meloxicam in Humans 0-6 ), or any AUC bounded by or in the range between any of these values. 0-6 It may also result in:

[0075] In some embodiments, the dosage form comprises a concentration of about 10-2500 ng / mL, about 100-2250 ng / mL, about 500-2000 ng / mL, about 1000-2500 ng / mL, about 1000-2000 ng / mL, about 100-900 ng / mL, about 750-1500 ng / mL, about 1250-2000 ng / mL, about 1500-2300 ng / mL, about 800-1200 ng / mL, about 1900-2400 ng / mL, about 2000 ng / mL, about 2500 ng / mL, about 3000 ng / mL, about 4000 ng / mL, about 5000 ng / mL, about 6000 ng / mL, about 7000 ng / mL, about 8000 ng / mL, about 9000 ng / mL, about 10000 ng / mL, about 15000 ng / mL, about 16000 ng / mL, about 17000 ng / mL, about 18000 ng / mL, about 20000 ng / mL, about 25000 ng / mL, about 30000 ng / mL, about 40000 ng / mL, about 50000 ng / mL, about 60000 ng / mL, about 70000 ng / mL, about 80000 ng / mL, about 90000 ng / mL, about 10000 ng / mL, about 12000 ng / mL, about 14000 ng / mL, about 15000 ng / mL, about 16000 ng / mL, about 170 ng / mL, about 50-500ng / mL, about 400-950ng / mL, about 900-1500ng / mL, about 1100-2200ng / mL, about 1300-1600ng / mL, about 1200-150 0ng / mL, about 1400-2100ng / mL, about 1500-1900ng / mL, about 1600-2100ng / mL, about 1700-2000ng / mL, about 1900-2500ng / mL, about 15 00-1700ng / mL, about 1600-1800ng / mL, about 1700-1900ng / mL, about 1800-2000ng / mL, about 1900-2100ng / mL, about 2000-2200ng / mL, about 2100-2300ng / mL, about 2200-2400ng / mL, about 2300-2500ng / mL, about 2500-3000ng / mL, at least about 1400ng / mL, at least about C of meloxicam of 1500 ng / mL, at least about 1600 ng / mL, at least about 1700 ng / mL, at least about 1800 ng / mL, at least about 1900 ng / mL, at least about 2000 ng / mL, at least about 2100 ng / mL, at least about 2200 ng / mL, at least about 2300 ng / mL, at least about 2400 ng / mL, at least about 2500 ng / mL max (Mean, Mean, or Average C of Meloxicam in Humans max ), or any C bounded by or in the range between these values max It may also result in:

[0076] In some embodiments, the dosage form comprises a concentration of about 10-2500 ng / mL, about 100-2250 ng / mL, about 500-2000 ng / mL, about 1000-2500 ng / mL, about 1000-2000 ng / mL, about 100-900 ng / mL, about 750-1500 ng / mL, about 1250-2000 ng / mL, about 1500-2300 ng / mL, about 800-1200 ng / mL, about 1900-2400 ng / mL, about 50-500 ng / mL, about 400-950 ng / mL, about 900-1500 ng / mL, about 1100-2200 ng / mL, about 1300-1600 ng / mL, about 120 C of frovatriptan of 0-1500ng / mL, about 1400-2100ng / mL, about 1500-1900ng / mL, about 1600-2100ng / mL, about 1700-2000ng / mL, about 1900-2500ng / mL, about 150-1700ng / mL, about 1600-1800ng / mL, about 1700-1900ng / mL, about 1800-2000ng / mL, about 1900-2100ng / mL, about 2000-2200ng / mL, about 2100-2300ng / mL, about 2200-2400ng / mL, about 2300-2500ng / mL, and about 2500-3000ng / mL max (Median, mean, or average C of frovatriptan in humans max ), or any C bounded by or in the range between these values max It may also result in:

[0077] For example, the methods described herein can be used to max (Mean, Mean, or Average T of Meloxicam in Humans maxIn some embodiments, the method may include treating a patient to reduce the amount of erythrocyte erythrocyte secretion in the patient within about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 180 minutes, about 10-30 minutes, about 20-40 minutes, about 30-50 minutes, about 40-6 ...100 minutes, about 110 minutes, about 120 minutes, about 130 minutes, about 140 Meloxicam T at about 50-70 minutes, about 60-90 minutes, about 70-100 minutes, about 80-110 minutes, about 90-120 minutes, about 1-10 hours, about 2-9 hours, about 3-7 hours, about 4-6 hours, about 1-5 hours, about 2-7 hours, about 3-8 hours, about 4-9 hours, about 1-4 hours, about 2-5 hours, about 3-6 hours, about 4-7 hours, about 5-8 hours, about 6-9 hours, about 7-10 hours max , or any T bounded by or in the range between these values. max It may include achieving:

[0078] In some embodiments, the oral dosage form provides a shorter T of meloxicam than is achieved by administration of meloxicam by intramuscular injection. max (Mean, Mean, or Average T of Meloxicam in Humans max In some embodiments, the oral dosage form may have a shorter T of meloxicam by a factor of at least about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 15, about 20, or by a factor of about 1.1-2, about 1.5-3, about 2-4, about 3-5, about 4-6, about 1.5-1000, about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about 12-100, about 15-100, about 20-100, or within a range bounded by any of these values, compared to that observed upon intramuscular injection. max or may increase meloxicam plasma levels at a faster rate.

[0079] In some embodiments, the oral dosage form may have a meloxicam plasma half-maximum time (median, mean, or average plasma half-maximum time in humans) that is less than about 5 minutes, less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, less than about 25 minutes, less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, less than about 60 minutes, less than about 90 minutes, about 5-15 minutes, about 10-20 minutes, about 15-25 minutes, about 20-30 minutes, about 25-35 minutes, about 30-45 minutes, about 35-50 minutes, about 40-55 minutes, about 45-60 minutes, about 0.5-5 hours, or a time within a range bounded by any of these values.

[0080] For example, the methods described herein may be used to treat frovatriptan T max (Median, Mean, or Average T of Frovatriptan in Humans max In some embodiments, the method may treat a patient to reduce the amount of erythrocyte erythrocyte secretion in the patient within about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 180 minutes, about 10-30 minutes, about 20-40 minutes, about 30-50 minutes, about 40-60 minutes, about 50-70 minutes, about 60-80 minutes, about 10 minutes, about 12 minutes, about 14 minutes, about 16 minutes, about 18 minutes, about 18 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 ...18 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 18 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about T of frovatriptan within about 70-90 minutes, about 0.1-1 hour, about 0.1-0.5 hours, about 0.5-1 hour, about 1-10 hours, about 2-9 hours, about 3-7 hours, about 4-6 hours, about 1-5 hours, about 2-7 hours, about 3-8 hours, about 4-9 hours, about 1-4 hours, about 2-5 hours, about 3-6 hours, about 4-7 hours, about 5-8 hours, about 6-9 hours, about 7-10 hours max , or any T bounded by or in the range between these values. max It may include achieving:

[0081] In some embodiments, the dosage form comprising meloxicam is about 0.01-0.5 μg / mL, about 0.5-0.7 μg / mL, about 0.6-0.8 μg / mL, about 0.7-0.9 μg / mL, about 0.8-1 μg / mL, about 0.01-1 μg / mL, about 0.9-1.1 μg / mL, about 1-1.2 μg / mL, about 1.1-1.3 μg / mL, about 1.2-1.4 μg / mL, about 1.3-1.5 μg / mL, about 1-1.5μg / mL, about 1.4-1.6μg / mL, about 1.5-1.7μg / mL, about 1.6-1.8μg / mL, about 1.7-1.9μg / mL, about 1.8-2μg / mL, about 1.5-2μg / mL, about 1.9-2.1μg / mL, about 2-2.2μg / mL, about 2.1-2.3μg / mL, about 2.2-2.4μg / mL, about 2.3-2.5μg / mL, about 2-2.5μg / mL, about 2.4- 2.6μg / mL, approximately 2.5-2.7μg / mL, approximately 2.6-2.8μg / mL, approximately 2.7-2.9μg / mL, approximately 2.8-3μg / mL, approximately 2.5-3μg / mL, approximately 2.9-3.1μg / mL , about 3-3.2μg / mL, about 3.1-3.3μg / mL, about 3.2-3.4μg / mL, about 3.3-3.5μg / mL, about 3-3.5μg / mL, about 3.4-3.6μg / mL, about 3.5-3. The compound may provide a 12-hour meloxicam plasma concentration (median, mean, or average meloxicam plasma concentration in humans) of about 7 μg / mL, about 3.6-3.8 μg / mL, about 3.7-3.9 μg / mL, about 3.8-4 μg / mL, about 3.5-4 μg / mL, or any 12-hour meloxicam plasma concentration bounded by or within the range between any of these values.

[0082] In some embodiments, meloxicam is administered at a concentration of about 0.01-0.5 μg / mL, about 0.5-0.7 μg / mL, about 0.6-0.8 μg / mL, about 0.7-0.9 μg / mL, about 0.8-1 μg / mL, about 0.01-1 μg / mL, about 0.9-1.1 μg / mL, about 1-1.2 μg / mL, about 1.1-1.3 μg / mL, about 1.2-1.4 μg / mL, about 1.3-1.5 μg / mL, about 1.4-1.6 μg / mL, about 1.5-1.7 μg / mL, about 1.6-1.8 μg / mL, about 1.8-1.9 μg / mL, about 1.9-2.1 μg / mL, about 2.1-2.2 μg / mL, about 2.2-2.3 μg / mL, about 2.3-2.4 μg / mL, about 2.4-2.5 μg / mL, about 2.5-2.6 μg / mL, about 2.6-2.7 μg / mL, about 2.7-2.8 μg / mL, about 2.8-3.1 μg / mL, about 2.8-3.2 μg / mL, about 2.8-3.3 μg / mL, about 2.8-3.4 μg / mL, about 2.8-3.5 μg / mL, about 2.8-3.6 μg / mL, about 2.8-3.7 μg / mL, about 2.8-3.8 μg / mL, about 2.8-3.9 μg / mL, about 2.9-3.4 μg / mL, about 2.9-3.5 μg / mL, about 2.9-3.6 μg / mL, about 2.9-3.7 μg g / mL, approximately 1.7-1.9μg / mL, approximately 1.8-2μg / mL, approximately 1-2μg / mL, approximately 0.01-3μg / mL, approximately 1.9-2.1μg / mL, approximately 2-2.2μg / mL, approximately 2.1-2.3μg / mL, approximately 2.2-2.4μ g / mL, about 2.3-2.5μg / mL, about 2.4-2.6μg / mL, about 2.5-2.7μg / mL, about 2.6-2.8μg / mL, about 2.7-2.9μg / mL, about 2.8-3μg / mL, about 2-3μg / mL, about 2.9-3. 1μg / mL, about 3-3.2μg / mL, about 3.1-3.3μg / mL, about 3.2-3.4μg / mL, about 3.3-3.5μg / mL, about 3.4-3.6μg / mL, about 3.5-3.7μg / mL, about 3.6-3.8μg / mL, Approximately 3.7-3.9μg / mL, approximately 3.8-4μg / mL, approximately 3-4μg / mL, approximately 2-4μg / mL, approximately 0.01-4μg / mL, approximately 0.1-20μg / mL, approximately 0.5-15μg / mL, approximately 0.5-10μg / mL, approximately 5-15 Meloxicam average plasma levels (C ave or average plasma level), or any meloxicam average plasma level bounded by or within the range between any of these values.

[0083] In some embodiments, the dosage form containing frovatriptan has a concentration of about 0.01-0.5 μg / mL, about 0.5-0.7 μg / mL, about 0.6-0.8 μg / mL, about 0.7-0.9 μg / mL, about 0.8-1 μg / mL, about 0.9-1.1 μg / mL, about 1-1.2 μg / mL, about 1.1-1.3 μg / mL, about 1.2-1.4 μg / mL , about 1.3-1.5μg / mL, about 1.4-1.6μg / mL, about 1.5-1.7μg / mL, about 1.6-1.8μg / mL, about 1.7-1.9μg / mL, about 1. 8-2μg / mL, about 1.9-2.1μg / mL, about 2-2.2μg / mL, about 2.1-2.3μg / mL, about 2.2-2.4μg / mL, about 2.3-2.5μg / 2.4-2.6 μg / mL, about 2.5-2.7 μg / mL, about 2.6-2.8 μg / mL, about 2.7-2.9 μg / mL, about 2.8-3 μg / mL, about 2.9-3.1 μg / mL, about 3-3.2 μg / mL, about 3.1-3.3 μg / mL, about 3.2-3.4 μg / mL, about 3.3-3.5 μg / mL, about 3.4-3.6 μg / mL, about 3.5-3.7 μg / mL, about 3.6-3.8 μg / mL, about 3.7-3.9 μg / mL, about 3.8-4 μg / mL, or any 12-hour frovatriptan plasma concentration bounded by or within the range between any of these values.

[0084] In some embodiments, frovatriptan is at about 0.01-0.5 μg / mL, about 0.5-0.7 μg / mL, about 0.6-0.8 μg / mL, about 0.7-0.9 μg / mL, about 0.8-1 μg / mL, about 0.9-1.1 μg / mL, about 1-1.2 μg / mL, about 1.1-1.3 μg / mL, about 1.2-1.4 μg / mL, about 1.3-1.5 μg / mL, about 1.4-1.6 μg / mL, about 1.5-1.7 μg / mL, about 1.6-1.8μg / mL, about 1.7-1.9μg / mL, about 1.8-2μg / mL, about 1.9-2.1μg / mL, about 2-2.2μg / mL, about 2.1-2.3μg / mL, about 2.2-2.4μg / mL, about 2.3-2.5μg / mL, about 2.4-2.6μg / mL, about 2.5-2.7μg / mL, about 2.6-2.8μg / mL, about 2.7-2.9μg / mL, about 2.8-3μg / mL, about 2.9-3.1μg / mL , about 3-3.2 μg / mL, about 3.1-3.3 μg / mL, about 3.2-3.4 μg / mL, about 3.3-3.5 μg / mL, about 3.4-3.6 μg / mL, about 3.5-3.7 μg / mL, about 3.6-3.8 μg / mL mL, about 3.7-3.9μg / mL, about 3.8-4μg / mL, about 0.1-20μg / mL, about 0.5-15μg / mL, about 0.5-10μg / mL, about 5-15μg / mL, about 10-20μg / mL, about 7. Average frovatriptan plasma levels (C) of 5-15 μg / mL, about 2-10 μg / mL, about 1-8 μg / mL, about 1-6 μg / mL, about 1-2 μg / mL, about 0.5-3.5 μg / mL, about 0.5-7 μg / mL, about 12-20 μg / mL, about 8-12 μg / mL, about 1-4 μg / mL, about 4-7 μg / mL, about 7-11 μg / mL, about 11-15 μg / mL, about 15-19 μg / mL, and about 16-20 μg / mL ave or average plasma level), or any amount within the range bounded by or between any of these values.

[0085] In some embodiments, the dosage form may be formulated for oral administration, for example, with an inert diluent or an edible carrier, enclosed in a hard or soft gelatin capsule, compressed into a tablet, or incorporated directly into the diet. For oral therapeutic administration, the active compound may be incorporated into excipients and used in the form of ingestible tablets, buccal tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches, and the like.

[0086] Tablets, troches, pills, capsules, etc. may also contain one or more of the following: binders (such as tragacanth gum, acacia, corn starch, or gelatin), additives (such as dibasic calcium phosphate), disintegrants (such as corn starch, potato starch, alginic acid, etc.), lubricants (such as magnesium stearate), sweeteners (such as sucrose, lactose, or saccharin), and flavoring agents (such as peppermint, wintergreen oil, or cherry flavoring). When the unit dosage form is a capsule, it may contain a liquid carrier in addition to the above-mentioned types of materials. Various other materials may be present as coatings, for example, tablets, pills, or capsules may be coated with cerac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetener, methylparaben and propylparaben as preservatives, a dye, and flavoring such as cherry flavoring or orange flavoring. It can also be desirable for materials in a dosage form or pharmaceutical composition to be pharma- ceutical pure and substantially non-toxic in the amounts employed.

[0087] In addition to meloxicam, cyclodextrin, triptan, and bicarbonate, some dosage forms may contain additives such as microcrystalline cellulose (e.g., about 1-20%), starch (e.g., about 1-10%), fumed silica (e.g., 0.1-10%), polyvinylpyrrolidone (e.g., about 1-10%), and / or magnesium stearate (e.g., about 0.1-10%).

[0088] Some compositions or dosage forms may be liquid or may comprise a solid phase dispersed in a liquid.

[0089] The dosage form may further comprise an additional pharma- ceutical active agent, such as an antacid or analgesic.

[0090] In some embodiments, the dosage form may further comprise an antacid present in an amount effective to raise the gastric pH of a patient to at least 2, at least 2.5, at least 3, at least 3.5, at least 4, and even at least 5 when one or more unit dosage forms are administered. The term "antacid" refers to an agent that reduces gastric acid secretion and raises gastric pH. Available specific H 2 Blocker (H 2 Antagonist or histamine H 2 Blockers or histamine H 2 Anti-inflammatory drugs (also referred to as antagonists) include, but are not limited to, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, famotidine, or combinations thereof.

[0091] Other drugs that can be effectively used as antacids are proton pump inhibitors, such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazole, and tenatoprazole. In some embodiments, the daily dose of the antacid, such as esomeprazole, is about 1-200 mg, about 1-100 mg, about 50-100 mg, about 1-50 mg, about 40-80 mg, about 5-50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about 20-40 mg, about 15-50 mg, about 30-60 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or any other amount within the range bounded by or between any of these values.

[0092] Examples of specific proton pump inhibitors include esomeprazole (in an amount between 5 mg and 50 mg in a unit dosage form), omeprazole (in an amount between 5 mg and 50 mg in a unit dosage form), lansoprazole (in an amount between 5 mg and 150 mg (preferably between 5 mg and 30 mg) in a unit dosage form), and pantoprazole (in an amount between 10 mg and 200 mg in a unit dosage form). In some embodiments, the proton pump inhibitor (such as esomeprazole) is present in the dosage form in an amount of about 10-30 mg, about 20-40 mg, about 30-50 mg, about 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90 mg, or about 80-100 mg. Recently, a new class of antacids has been developed that compete with potassium for the acid pump. Compounds of this type are called "reversible proton pump inhibitors" or "acid pump antagonists" and can also be used. Examples include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan, and soraprazan (see WO 9605177, WO 9605199). Other compounds of this type include H-335 / 25 (AstraZeneca, Dialog File 128, Accession No. 020806), Sch-28080 (Schering Plough, Dialog File 128, Accession No. 009663), Sch-32651 (Schering Plough, Dialog File 128, Accession No. 006883), and SK&F-96067 (CAS Registry No. 115607-61-9).

[0093] Additional therapeutically active agents include analgesics such as a second nonsteroidal anti-inflammatory drug, an opioid, a steroid, a triptan, etc. In some embodiments, the dosage form or treatment further comprises administering an effective amount of a second nonsteroidal anti-inflammatory drug to reduce or eliminate pain or inflammation. For purposes of this disclosure, reference to an antacid, an NSAID, or an analgesic should be understood to include all conventional forms of these compounds, particularly their pharma- ceutically acceptable salts. The amount of pharma-ceutically effective NSAID may be less in this embodiment than in other applications due to potential positive kinetic interactions and NSAID absorption in the presence of an antacid and / or buffer.

[0094] In another embodiment, the dosage form or treatment further comprises administering an effective amount of an opioid to reduce or eliminate pain or inflammation, including, but not limited to, (dextro)propoxyphene, A-methylfentanyl, alfentanil, allylprozine, benzitramide, buprenorphine, butorphanol, carfentanil, desmethylprozine, dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone, dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl, ketobemidone, lefetamine ... Basetilmethadol, levomethorphan, levorphanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone, nicomorphine, omefentanil, oripavine, oxycodone, oxymorphone, PEPAP, paramorphine, pentazocine, phenazocine, piritramide, prodine, remifentanil, sufentanil, tapentadol, tilidine, tramadol, or combinations thereof.

[0095] The term "unit dosage form" is used herein to refer to a single entity for administration of a drug. For example, a single tablet or capsule combining both a triptan and an NSAID is a unit dosage form. A "unit dosage form" may also be referred to as a "fixed dosage form" or a "fixed dose combination", which are otherwise interchangeable. In one embodiment, the unit dosage form is a multi-layer tablet.

[0096] In another embodiment, the unit dosage form is suitable for oral administration to a patient. In yet another embodiment, the unit dosage form is a tablet. In yet another embodiment, the unit dosage form is a multi-layer tablet comprising a single core and one or more layers external to the core. In some embodiments, the pharmaceutical composition may comprise a triptan (such as rizatriptan or frovatriptan), a cyclodextrin, and a bicarbonate in an amount effective to increase the bioavailability of the rizatriptan or frovatriptan. In another embodiment, the pharmaceutical composition may comprise a triptan (such as rizatriptan or frovatriptan), a cyclodextrin, and a bicarbonate in an amount effective to increase the bioavailability of the triptan or to increase the T of the triptan. max The drug may have an effective amount of triptan, sulfobutylether-β-cyclodextrin (SBEβCD), and sodium bicarbonate to reduce

[0097] Some dosage forms may include a first layer comprising meloxicam, SBEβCD and a bicarbonate, and a second layer comprising a triptan and a bicarbonate.

[0098] The first layer may, for example, contain meloxicam in an amount within one of the ranges described above. For example, all of the meloxicam in the dosage form may be present in the first layer. The second layer may contain all of the triptan, such that an amount within one of the ranges described above for the triptan may be applied to the second layer.

[0099] In some embodiments, the first layer contains about 10-200 mg, about 50-150 mg, about 50-100 mg, about 70-120 mg, about 90-140 mg, or about 100 mg of a bicarbonate (such as sodium bicarbonate), or any amount within a range bounded by any of these values.

[0100] In some embodiments, the second layer contains about 100-500 mg, about 200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, or about 400 mg of a bicarbonate (such as sodium bicarbonate), or any amount within a range bounded by any of these values.

[0101] Some oral dosage forms may have an enteric coating or a film coating. In some embodiments, the dosage form may include a tablet or capsule with an enteric coating. In some embodiments, the dosage form may include a tablet or capsule with a film coating.

[0102] One embodiment of the disclosure is a pharmaceutical composition in unit dosage form suitable for administration to a patient, comprising: (a) dexketoprofen, with or without an enteric coating; (b) sodium or potassium bicarbonate and / or sodium or potassium carbonate, and (c) frovatriptan, with or without an enteric coating, and with or without being formulated with cyclodextrin; The present invention relates to a pharmaceutical composition comprising:

[0103] In certain embodiments, the pharmaceutical compositions provide a more rapid release or dissolution of a drug (e.g., meloxicam or other NSAIDs, rizatriptan, frovatriptan, or other triptans) from the dosage form compared to a dosage form containing the same drug but that does not contain an antacid or that does not contain a buffer.

[0104] Contemplated embodiments are listed below.

[0105] Embodiment 1 An inclusion complex of meloxicam in a cyclodextrin. Embodiment 2 A dosage form comprising 1) the inclusion complex of embodiment 1 or 2) meloxicam and a carbonate or bicarbonate. Embodiment 3. The dosage form of embodiment 2 comprising an inclusion complex, wherein the cyclodextrin comprises a substituted β-cyclodextrin. Embodiment 4. The dosage form of embodiment 3, wherein the substituted β-cyclodextrin is sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropyl β-cyclodextrin (HPβCD). Embodiment 5. The dosage form of embodiment 4, wherein the cyclodextrin is SBEβCD. Embodiment 6. The dosage form of embodiment 5, wherein said SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin. Embodiment 7. The dosage form of embodiment 6, wherein said meloxicam and said SBEβCD have a molar ratio of about 0.8 to about 1.2. Embodiment 8. The dosage form of embodiment 6, wherein said meloxicam and said SBEβCD have a molar ratio of about 1. Embodiment 9. The dosage form of embodiment 2, 3, 4, 5, 6, 7, or 8, which contains a bicarbonate. Embodiment 10. The dosage form of embodiment 9, wherein the bicarbonate comprises sodium bicarbonate. Embodiment 11 The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is an oral dosage form. Embodiment 12. The dosage form of embodiment 2, 3, 4, 5, 6, 9, 10, or 11, wherein about 50 mg to about 200 mg of SBEβCD is present in the dosage form. Embodiment 13. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the carbonate or bicarbonate is present in an amount ranging from about 400 mg to about 600 mg. Embodiment 14 T of meloxicam max is reduced compared to a dosage form that does not contain a carbonate, bicarbonate, or cyclodextrin. Embodiment 15 The T max is achieved in the patient at a time within the range of about 10 minutes to about 180 minutes after administration. Embodiment 16 The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, which has a higher oral bioavailability of meloxicam than a dosage form that does not contain a carbonate, a bicarbonate, or a cyclodextrin. Embodiment 17. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, further comprising an antacid. Embodiment 18. The dosage form of embodiment 17, wherein the antacid is a proton pump inhibitor. Embodiment 19. The dosage form of embodiment 18, wherein the proton pump inhibitor is esomeprazole. Embodiment 20. The dosage form of embodiment 19, wherein about 30 mg to about 50 mg of esomeprazole is present in the dosage form. Embodiment 21 A method of orally administering meloxicam comprising orally administering the dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 to a patient in need of such treatment. Embodiment 22. The method of embodiment 21, wherein the dosage form is administered to treat pain. Embodiment 23. The method of embodiment 21, wherein the dosage form is administered to treat inflammatory pain. Embodiment 24 The method of embodiment 21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis. Embodiment 25 A method of intravenously administering meloxicam comprising intravenously administering the dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 to a patient in need of such treatment. Embodiment 26. An inclusion complex of frovatriptan in a cyclodextrin.

[0106] Embodiment 2-1: A dosage form comprising 1) an inclusion complex of frovatriptan in a cyclodextrin, or 2) frovatriptan and a carbonate or bicarbonate. Embodiment 2-2 The dosage form of embodiment 2-1 comprising an inclusion complex, wherein the cyclodextrin comprises sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropyl β-cyclodextrin (HPβCD). Embodiment 2-3 The dosage form of embodiment 2-2, wherein said cyclodextrin is SBEβCD and has about 6 to about 7 sulfobutyl ether groups per molecule of β-cyclodextrin. Embodiments 2-4 The dosage form of embodiment 2-3 further comprising a bicarbonate. Embodiments 2-5. The dosage form of embodiment 2-4, wherein the bicarbonate comprises sodium bicarbonate. Embodiments 2-6 The dosage form of embodiment 2-3, wherein said frovatriptan and said SBEβCD have a molar ratio of about 0.8 to about 1.2. Embodiments 2-7. The dosage form of embodiment 2-6, which contains a bicarbonate. Embodiments 2-8. The dosage form of embodiment 2-7, wherein the bicarbonate comprises sodium bicarbonate. Embodiment 2-9 The dosage form of embodiment 2-1, which is an oral dosage form. Embodiment 2-10. The dosage form of embodiment 2-2 comprising an inclusion complex, wherein said inclusion complex is present in a unit dosage form from about 50 mg to about 200 mg of said SBEβCD. Embodiment 2-11 The dosage form of embodiment 2-1 comprising said frovatriptan and said carbonate or said bicarbonate. Embodiment 2-12 T of Frovatriptan max The dosage form of embodiment 2-1, wherein the amount of cyclodextrin in the carbonate, bicarbonate, or cyclodextrin in the cyclodextrin is reduced compared to a dosage form that does not contain a carbonate, bicarbonate, or cyclodextrin. Embodiment 2-13 T of Frovatriptan max The dosage form of embodiment 2-1, wherein the .DELTA.I.times. ... Embodiment 2-14 The dosage form of embodiment 2-1 having a higher oral bioavailability of frovatriptan than a dosage form that does not contain a carbonate, a bicarbonate, or a cyclodextrin. Embodiments 2-15. The dosage form of embodiment 2-11, wherein said carbonate or said bicarbonate is present in the unit dosage form in an amount ranging from about 400 mg to about 600 mg. Embodiments 2-16. The dosage form of embodiment 2-15, wherein the carbonate or bicarbonate is sodium bicarbonate. Embodiments 2-17. The dosage form of embodiment 2-11, further comprising an NSAID. Embodiments 2-18. The dosage form of embodiment 2-17, wherein the NSAID is dexketoprofen or meloxicam. Embodiments 2-19. The dosage form of embodiment 2-18, wherein the NSAID is dexketoprofen. Embodiments 2-20. The dosage form of embodiment 2-19, wherein from about 10 mg to about 50 mg of dexketoprofen is present in the unit dosage form. Embodiment 2-21 A method for orally administering frovatriptan comprising orally administering the dosage form of embodiment 2-1 to a patient in need of treatment. Embodiments 2-22 The method of any one of embodiments 2-21, wherein the dosage form comprises the inclusion complex, the cyclodextrin is SBEβCD, and the dosage form further comprises a bicarbonate. Embodiments 2-23. The method of embodiment 2-22, wherein the bicarbonate is sodium bicarbonate. Embodiments 2-24. The method of any of embodiments 2-23, wherein the unit dosage form contains from about 300 mg to about 600 mg of sodium bicarbonate. Embodiments 2-25 The method of embodiment 2-22, wherein the dosage form further comprises an NSAID. Embodiments 2-26 The method of any of embodiments 2-25, wherein said NSAID is dexketoprofen, meloxicam, naproxen, ibuprofen, or celecoxib. Embodiments 2-27 The method of embodiment 2-21, wherein the dosage form is administered to treat pain. Embodiments 2-28 The method of embodiment 2-21, wherein the dosage form is administered to treat inflammatory pain. Embodiments 2-29 The method of embodiment 2-21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

[0107] Embodiment P-1 A dosage form comprising meloxicam, sulfobutyl ether β-cyclodextrin (SBEβCD), a bicarbonate, and a triptan, which has a shorter T of meloxicam than a reference dosage form that 1) contains the same amount of meloxicam, 2) does not contain SBEβCD, and 3) does not contain bicarbonate. max The dosage form is an oral dosage form having the formula: Embodiment P-2 The dosage form of embodiment P-1 comprising an inclusion complex of 1) said meloxicam or said triptan and 2) said SBEβCD. Embodiment P-3 The dosage form of embodiment P-1 or P-2 containing about 10 mg to about 20 mg of meloxicam. Embodiment P-4 The dosage form of embodiment P-3 containing about 15 mg of meloxicam. Embodiment P-5. The dosage form of embodiment P-1, P-2, P-3, or P-4, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin. Embodiment P-6 The dosage form of embodiment P-1, P-2, P-3, P-4, or P-5 containing about 50 mg to about 200 mg of said SBEβCD. Embodiment P-7 The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, or P-6, wherein the triptan is rizatriptan. Embodiment P-8 The dosage form of embodiment P-7 containing about 5 mg to about 20 mg of rizatriptan. Embodiment P-9 The dosage form of embodiment P-8 containing about 10 mg of rizatriptan. Embodiment P-10 The dosage form of embodiment P-6 containing about 100 mg of SBEβCD. Embodiment P-11 The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, or P-10, wherein the bicarbonate comprises sodium bicarbonate. Embodiment P-12 The dosage form of embodiment P-10 containing about 400 mg to about 600 mg of bicarbonate. Embodiment P-13 The dosage form of embodiment P-12 containing about 500 mg of sodium bicarbonate. Embodiment P-14 The oral dosage form has a mean T of meloxicam of less than about 3 hours. max The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, or P-12, wherein the dosage form is shown to have Embodiment P-15 The oral dosage form has a mean T of meloxicam of less than about 2 hours. max The dosage form of embodiment P-14, wherein Embodiment P-16 The oral dosage form has a mean T of meloxicam of less than about 1 hour. max The dosage form of embodiment P-14, wherein Embodiment P-17. The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, or P-16, wherein the oral dosage form has an increased bioavailability of meloxicam when administered to a mammal compared to the reference dosage form. Embodiment P-18. The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, or P-17, wherein the oral dosage form has improved pharmacokinetics of meloxicam when administered to a mammal compared to the reference dosage form. Embodiment P-19. The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, or P-18, wherein the oral dosage form has increased bioavailability of the triptan when administered to a mammal compared to the reference dosage form. Embodiment P-20. The dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, P-18, or P-19, wherein the oral dosage form has improved pharmacokinetics of the triptan when administered to a mammal compared to the reference dosage form. EMBODIMENT P-21 A method of improving the pharmacokinetics of a triptan or NSAID comprising orally administering a dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, P-18, P-19, or P-20 to a mammal or human in need of treatment with the triptan or NSAID. Embodiment P-22 A method of treating pain comprising orally administering a dosage form of embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, P-18, P-19, or P-20 to a mammal or human in need thereof. Embodiment P-23 The method of embodiment P-22, wherein said pain is a migraine headache. Embodiment P-24 The method of embodiment P-22, wherein said pain is inflammatory pain.

[0108] Example 1 Various amounts of potassium carbonate (K) at acidic medium pH 2 CO 3 ) and sodium bicarbonate (NaHCO 3 The effect of K on the microbial activity of the bacteria was investigated. The acidic medium was chosen to mimic gastric conditions. 2 CO 3 or NaHCO 3 K was added. 2 CO 3 or NaHCO 3 After the addition, the pH of the solution was measured. Deionized water (240 mL) was then added to the mixture, and the pH was measured again. The results are shown in Tables 1 to 4.

[0109] [Table 1]

[0110] [Table 2]

[0111] [Table 3]

[0112] [Table 4]

[0113] Example 2 Contains meloxicam and cyclodextrin, K 2 CO 3 , or NaHCO 3 Tablets containing meloxicam alone (MOBIC®) were also purchased and tested for solubility. The tablets tested are listed in Table 5. For tablets containing meloxicam and cyclodextrin, meloxicam was used in the form of a meloxicam / cyclodextrin inclusion complex. The inclusion complex was formed by mixing meloxicam and cyclodextrin in a pH adjusted aqueous solution. The pH of the solution was adjusted with a buffer. The resulting soluble meloxicam / cyclodextrin inclusion complex was then spray dried. The spray dried dispersion was used to prepare tablets containing cyclodextrin.

[0114] [Table 5]

[0115] Dissolution tests in acidic medium (selected to mimic gastric conditions) were performed by placing the tablets in 0.01 N HCl solution at an agitation speed of 75 RPM and a vessel temperature of approximately 37° C. The results are shown in Table 6 and Figures 1 to 10. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are shown as the percentage (%) of meloxicam dissolved.

[0116] [Table 6]

[0117] The solubility of meloxicam was significantly improved in tablets containing meloxicam, cyclodextrin, and K, compared to tablets containing only meloxicam. 2 CO 3 , or NaHCO 3 The results were greater for tablets containing various combinations of NaHCO 3 After 120 minutes, the dissolution rate of the meloxicam tablets containing was 95% compared to 2% for the tablets containing meloxicam alone.

[0118] The solubility of meloxicam in the absence of cyclodextrin is 2 CO 3 However, in the presence of cyclodextrin, K 2 CO 3 Increasing the amount of potassium carbonate does not appear to increase meloxicam solubility. Even at the highest potassium carbonate dose, meloxicam solubility in the presence of cyclodextrin was reduced by approximately 50% compared to meloxicam solubility at 120 min in the absence of cyclodextrin.

[0119] NaHCO 3 The solubility of meloxicam with 2 CO 3 The solubility of meloxicam in the presence of cyclodextrin was also significantly higher than that observed at the doses (50% vs. 30% at 15 min and 92% vs. 23% at 120 min). 3 When accompanied by 2 CO3 The solubility was significantly higher than that observed with the cyclodextrin-containing NaHCO solubility test (85% vs. 26% at 15 min and 86% vs. 12% at 120 min). 3 increased meloxicam solubility at 15 min compared to potassium bicarbonate which resulted in a decrease in solubility.

[0120] Example 3 A bilayer tablet was prepared containing 1) an inclusion complex of SBEβCD with meloxicam prepared as described in Example 2, and 2) sodium bicarbonate (SBEβCD-meloxicam / bicarbonate). The first layer contained 15 mg of meloxicam inclusion complex with 100 mg of SBEβCD and 100 mg of sodium bicarbonate. The second layer contained 40 mg of esomeprazole and 400 mg of sodium bicarbonate.

[0121] A total of 20 human subjects were randomly assigned in a 1:1 ratio to receive either SBEβCD-meloxicam / bicarbonate tablets as described above or Mobic® tablets (meloxicam 15 mg) once daily for 6 days under fasting conditions.

[0122] Plasma samples were collected on the first day of dosing for analysis of meloxicam concentrations at multiple time points. Meloxicam concentrations were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. Results are shown in Figure 11.

[0123] The primary endpoint of the study was median T max was 9 times faster with SBEβCD-meloxicam / bicarbonate tablets compared to Mobic® (0.5 vs. 4.5 hours, respectively, p<0.0001).

[0124] Additionally, SBEβCD-meloxicam / bicarbonate tablets showed higher mean maximum plasma concentrations (C max) (p=0.0018), more rapid time to therapeutic plasma concentration (p<0.0001), and more rapid time to half-maximum plasma concentration (p<0.0001).

[0125] Example 4 A monolayer tablet was prepared containing 1) an inclusion complex of SBEβCD with meloxicam, 2) rizatriptan, and 3) sodium bicarbonate (SBEβCD-meloxicam / rizatriptan / bicarbonate). The monolayer tablet contained 20 mg meloxicam, 10 mg rizatriptan, and 500 mg sodium bicarbonate. The inclusion complex was the same as that of Example 3.

[0126] Dissolution testing of the tablets in acidic medium (selected to mimic gastric conditions) was performed by placing the tablets in 0.01 N HCl solution at an agitation speed of 75 RPM and a vessel temperature of approximately 37° C. The results are shown in Table 7. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as percent (%) meloxicam dissolved and percent (%) rizatriptan dissolved.

[0127] [Table 7]

[0128] As shown in Table 7, the dissolution results of the tablets of Example 4 were very similar to those of Example 2. Therefore, the inventors investigated the pharmacokinetic properties (bioavailability, T max ) are believed to be similar to those described in Example 3 and FIG.

[0129] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weights, reaction conditions, and the like, used in the specification and claims are to be understood as referring in each instance to both the exact values ​​as indicated and those values ​​modified by the word "about". Accordingly, unless inconsistent, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. While not limiting the application of the doctrine of equivalents to the scope of the claims, at the very least, each numerical parameter should be construed as at least being approximated by applying ordinary rounding techniques based on the number of reported significant digits.

[0130] When describing the present invention (particularly in the claims), singular terms should be construed to include both the singular and the plural, unless otherwise specified herein and clearly contradicted by the context. All methods described herein can be performed in any suitable order, unless otherwise specified herein and clearly contradicted by the context. Any examples or illustrative statements (e.g., statements such as "etc.") described herein are merely intended to better clarify the present invention and are not intended to limit the scope of any claim. The description of the present invention should not be construed as referring to any element essential to the practice of the invention not described in the claims.

[0131] Groupings of alternative elements or embodiments described herein are not to be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or elements described herein. For convenience and / or patentability, one or more members of a group may be added to or deleted from a group. When such additions or deletions occur, the specification is considered to include the group so modified, thereby satisfying the description requirement of all Markush groups used in the claims.

[0132] A number of embodiments are described herein, including the best mode contemplated by the inventors for carrying out the invention. Of course, variations of the embodiments described herein will be apparent to those skilled in the art in light of the foregoing description. The inventors expect that such variations will be adopted by those skilled in the art as appropriate, and intend that the invention may be practiced other than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements is contemplated in all possible variations of the invention unless otherwise indicated herein and clearly contradicted by context.

[0133] Finally, it is to be understood that the embodiments described herein are intended to illustrate the principles of the claims. Other modifications that may be adopted are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be adopted in accordance with the teachings of this specification. Thus, the claims are not limited to the exact embodiments shown and disclosed.

Claims

[Claim 1] Meloxicam, Sulfobutyl ether β-cyclodextrin (SBEβCD), A dosage form containing a carbonate and a triptan, comprising: 1) an equal amount of meloxicam; 2) does not contain SBEβCD, and 3) does not contain bicarbonate, compared to a reference dosage form. Meloxicam has a shorter T ｍａｘ The dosage form is an oral dosage form having the formula:

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